3- Chloropyrazine 1-oxide with phosphoryl chloride

Regioselectivity in the chlorination of pyrazine /V-oxides with phosphoryl chloride depends upon the substituent on the C-3 carbon. Thus, 3-aminopyrazine 1-oxide is chlorinated with loss of the /V-oxide oxygen to give 2-amino-3-chloropyrazine as the sole product whereas 3-methoxy and 3-chloropyrazine 1-oxides form approximately equal amounts of 3-chloro- and 6-chloro-2-substituted pyrazines along with a trace of the 5-chloro derivatives. 

With the exception of those halogenopyrazines made by primary synthesis (see Chapters 1 and 2), most chloropyrazines have been made recently by the reaction of tautomeric pyrazinones with a phosphorus chloride or by the reaction of pyrazine iV-oxides with phosphoryl chloride in contrast, most other halogenopyrazines have been made by direct halogenation or by transhalogenation of chloropyrazines. A single interesting example of the conversion of a methoxy- into a chloropyrazine is included at the end of Section 4.1.1. 

Palamidessi and Bernardi have obtained 2-chloropyrazine 1-oxide by mild treatment of pyrazine 1,4-dioxide with phosphoryl chloride. The structure of the 1-oxide was confirmed by hydrolysis to 2-hydroxy-pyrazine 1-oxide, which was also prepared by direct synthesis from glyoxal and glycine hydroxamic acid.398 This synthesis is illustrative of a general method for preparing 2-hydroxypyrazine 1-oxides by condensation of a,/3-dicarbonyl compounds with a-aminohydroxamic acids. An analogous synthesis of 2-aminopyrazine 1-oxides has already... 

Pyrazine 1,4-dioxide reacts exothermically with phosphoryl chloride if, after the initial reaction has subsided, reaction is completed by heating under reflux, 2,6-dichloropyrazine is obtained.301,362 Elina and Musatova report that reaction of the dioxide with benzene sulfonyl chloride gives 2-chloropyrazine 1-oxide, m.p. 131°-132°, in low yield.406 A melting point of 140w—146° has been reported by previous workers for this compound.398... 

A number of piperazine-2,5-diones (a-amino acid anhydrides ) has been converted to pyrazines by the action of phosphorus halides. Baxter and Spring (312) first described the conversion of isoleucine anhydride (45) with phosphoryl chloride to 2,5-di-s-butyl-3,6-dichloropyrazine (46, X = Cl) and 2,5-di-s-butyl-3-chloropyrazine (46, X = H), and of DL-alanine anhydride (47) similary to 2,5-dichloro-3,6-dimethylpyrazine (48, X = Q) and 3from alanine anhydride does not involve an oxidation step, whereas the formation of 2,5-dichloro-3,6-dimethylpyrazine involves the oxidation of an intermediate dihydropyrazine derivative. Treatment of DL-alanine anhydride with phosphoryl chloride in the presence of a tertiary base (dimethylaniline) gave only the monochloro derivative the intermediate dichlorodihydropyrazine presumably loses hydrogen chloride and gives the stable aromatic 3-chloro-2,5-dimethylpyrazine. 

Matsuura and co-workers (756) have reexamined the reactions of the A -oxides of 2,5-dimethylpyrazine and found that 2,5-dimethylpyrazine di-A -oxide (29) when heated with phosphoryl chloride at 160° gave 2,5-dichloro-3,6-dimethylpyrazine (6%) (30), 3-chloro-2,5-dimethylpyrazine 1-oxide (5%) (31), and 5-chloromethyl-2-methylpyrazine 1 -oxide (9%) (32). In addition small amounts of other chlorinated products, 3-chloro-2-chloromethyl-5-methylpyrazine (33) and 2,5-bischloromethyl-pyrazine (34), were identified. These authors also examined the action of p-tosyl chloride, methane sulfonyl chloride, and mixtures of phosphoryl chloride and concentrated sulfuric acid, but state that these did not give good results. Pyrazine 1-oxide and phosphoryl chloride have been shown to give 2reaction conditions it gave 2-chloropyrazine 1-oxide (757). Pyrazine 1,4-dioxide and benzenesulfonyl chloride also gave a low yield of 2-chloropyrazine 1-oxide (758). 

Carboxypyrazine 1-oxide heated with phosphoryl chloride at 40-50° for 15 minutes gave 2-carboxy-6-chloropyrazine (868-870), but Novacek et al. (839) claim that 3-carboxypyrazine 1-oxide refluxed with thionyl chloride for 5.5 hours, and the product treated with ammonia, gave 2-carbamoyl-5-chloropyrazine ( ). 

The most convenient synthesis of halogenopyrazines and -quinoxalines is by halogenation of pyrazinones and quinoxalinones with phosphoryl or other acid halides. A methoxy group is also displaced with phosphoryl chloride to yield chloropyrazine when the period of reaction is prolonged or the reaction is carried out at higher temperatures <78JHC665>. Chloro- and bromopyrazine N-oxides are obtained by diazotization of aminopyrazine A-oxides in concentrated hydrochloric acid and hydrobromic acid, respectively (see Section 6.03.5.4.2). 

Deoxidative chlorination of alkyl- or aryl-substituted pyrazine A -oxides with refluxing phosphoryl chloride for 1 h provides 76-78% yields of the chloropyrazines <1997MI1076>. 

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